1. Field of the Invention
The present invention relates generally to methods and apparatus for the electroporation of tissues and more specifically to such methods and apparatus for the treatment of benign prostatic hyperplasia.
2. Description of the Related Art
Though greater detail will follow in the discussion below, succinctly stated, the present invention provides apparatus and methods of providing treatment for the undesirable proliferation of cells in the prostate by killing the cells with electric field pulses of selected duration and strength to take advantage of a cellular event known as “electroporation.”
Electroporation
The biophysical phenomenon known as electroporation refers to the use of electric field pulses to induce microscopic pores—“electropores”—in the lipid cell membranes. Depending on the parameters of the electric pulses, an electroporated cell can survive the pulsing or die. The cause of death of an electroporated cell is believed to be a chemical imbalance in the cell, resulting from the fluid communication with the extra-cellular environment through the pores. For a given cell size, geometry, and orientation, the number of electropores—and their size—created in the cell by the applied electric field pulses depends on both the amplitude E of the electric field pulses and the duration t of the pulses. That is, for a given pulse duration t, no pores will be induced in the cell until the amplitude E reaches a certain lower limit. This limit is different for different cells, particularly, for cells of different sizes. The smaller the size of a cell, the higher the electric field required to induce pores and thus the higher the lower limit is. Above the lower amplitude E limit the number of pores and their effective diameter increases proportionally with both increasing field amplitude E and pulse duration t. Electroporation is observed for pulse durations in the range from tens of microseconds to hundreds of milliseconds.
Until the upper limit of electroporation is achieved, an electroporated cell can survive the pulsing and restore its viability thereafter. Above the upper limit the pore diameters and number of induced pores become too large for a cell to survive. The irreversibly chemically imbalanced cell cannot repair itself by any spontaneous or biological process and dies. To kill a cell a potential in the range of 2 to 4 V should be applied along the cell. The cell killing by electroporation is a probabilistic process. That is, increasing the number of applied pulses of duration t leads to an increased probability of cell killing, a probability increase that is approximately equal to the percentage increase in the total time duration of the applied electric pulses.
The survivability of electroporated cells depends significantly on their temperature. At higher temperature cells are more vulnerable to cell death by electroporation. Thus, the amplitude and duration of the electric pulses required for cell killing are lower. It is believed that this observation is explained by two underlying phenomena: at higher temperatures cells are less stable biochemically because of more intense metabolic activity; and, secondly, at elevated temperatures the strength of lipid membranes decreases, which facilitates creating larger pores or irreversible rupture of the cell membrane. At lower temperatures (about 10 to about 20 degrees Celsius) cells are more resistant to electroporation and can survive two to three times higher voltages than they can at body temperature.
The Prostate Gland and Benign Prostatic Hyperplasia
The prostate gland forms part of the male reproductive system. The prostate gland is located between the bladder and the rectum and wraps around the urethra, the tube that carries urine out from the bladder through the penis. The gland consists a dense fibrous capsule enclosing several lobes or regions. The prostate gland is generally composed of smooth muscles and glandular epithelial tissue. The glandular epithelial tissue produces prostatic fluid. The smooth muscles contract during sexual climax and squeeze the prostatic fluid into the urethra as the sperm passes through the ejaculatory ducts and urethra. Prostatic fluid secreted by the prostate gland provides nutrition for ejaculated spermatozoids increasing their mobility and improves the spermatozoids chances for survival after ejaculation by making the environment in the vaginal canal less acidic.
Anatomically, the prostate gland is usually described as including three glandular zones: the central, peripheral and transitional zones. The transitional zone is located right behind the place where the seminal vesicles merge with the urethra. This transitional zone tends to be predisposed to benign enlargement in later life.
The prostate reaches its normal size and weight (about 20 grams) soon after puberty. The size and weight of the prostate typically remain stable until the individual reaches his mid-forties. At this age, the prostate gland—typically in the transitional zone—begins to enlarge through a process of excessive cell proliferation known as benign prostatic hyperplasia (BPH). This overgrowth can occur in both smooth muscle and glandular epithelial tissues and has been attributed to a number of different causes, including hormones and growth factors as well as generally to the aging process.
Benign prostate hyperplasia can cause distressing urination symptoms. As the disease progresses the dense capsule surrounding the enlarging prostate prevents it from further expansion outward and forces the prostate to press against the urethra, partially obstructing the urine flow. The tension in the smooth muscles of the prostate also increases which causes further compression of the urethra and reduction of the urine flow. Some symptoms of BPH stem from the gradual loss of bladder function leading to an incomplete emptying of the bladder. The symptoms can include straining to urinate, a weak or intermittent stream, an increased frequency of urination, pain during urination, and incontinence—the involuntary loss of urine following an uncontrollable sense of urgency. These symptoms alone can negatively affect the quality of life of affected men. Left untreated, BPH can cause even more severe complications, such as urinary tract infection, acute urinary retention, and uremia.
Before age 40, only 10% of men have benign prostatic hyperplasia; but by age 80, about 80% have signs of this condition. Benign prostatic hyperplasia is the most common non-cancerous form of cell growth in men. About 14 million men in US have BPH, and about 375,000 new patients are diagnosed every year.
For many years, researchers have tried to find medications to shrink the prostate or at least stop its growth. Between 1992 and 1997, the FDA approved four drugs for treatment of BPH: finasteride, terazosin, tamsulosin, and doxazosin.
Finasteride inhibits production of hormone DHT. DHT is one of the hormones that have been found to be involved in prostate enlargement. Treatment with Finasteride has been shown to shrink the prostate in some men.
Terazosin, doxazosin, and tamsulosin belong to the class of drugs known as alpha-blockers. Alpha-blockers act by relaxing the smooth muscle of the prostate and bladder to improve urine flow and reduce bladder outlet obstruction. In men with severe symptoms, though, these medications are palliative only. They can delay but not prevent the eventual need for surgery.
Regardless of the efficacy of any drug treatment, the long term exposure to xenobiotic compounds may produce additional unwanted side effects that are not realized until years after treatment. Accordingly, a need exists for an apparatus and method for the treatment of BPH that does not require the introduction of xenobiotic compounds.
For men with the most severe symptoms, surgery is generally considered to be the best long-term solution. There are several surgical procedures that have been developed for relieving symptoms of BPH. Each of these procedures, however, suffers from one or more of the following deficiencies: high morbidity, long hospital stays, the use of general anesthesia, significant side effects such as impotence, and possible complications such as infection and inflammation.
In recent years, a number of procedures have been introduced that are less invasive than surgery. One such procedure is transurethral microwave thermal therapy. In transurethral microwave thermal therapy, a Foley-type catheter containing a microwave antenna is placed within the urethra. The microwave antenna is positioned adjacent to the transitional zone of the prostate, where BPH occurs, and allows selective heating of the prostate. Maintaining the temperature of the BPH tissue above 45 degrees C. during about a one hour session leads to necrosis of the tissues and subsequent reabsorption of necrotic tissue by the body.
Another recently developed non-invasive technique is transurethral needle ablation (TUNA). TUNA uses low level radio frequency (RF) energy to heat the prostate. Using TUNA, two separate needles are inserted into prostate through the urethra. Several watts of RF energy is applied to each needle to cause thermal necrosis of the prostate cells around the needles. Application of this treatment to several sites of the prostate typically results in sufficient necrosis to relieve symptoms of the BPH.
While generally successful, the microwave and RF therapies are relatively long procedures. Also, because of the poor temperature control of the heated volume, the volume of removed tissue is often not sufficient for the long term relief of the symptoms and/or the healthy tissue of the urethra is damaged. A damaged urethra is capable of restoring itself, but the healing is a long morbid process accompanied by sloughing of the necrotic tissue into urethra and excretion of it during urination.
Therefore, a need exists for a minimally invasive therapy for treatment of BPH that requires shorter treatment times and is less morbid than existing therapies.